APPLICANT'S OVERALL DESCRIPTION Photodynamic therapy (PDT) is approaching its coming of age as a cancer treatment with regulatory approvals and new applications emerging around the world. The treatment is inherently complex involving many variables such as drug and light dose, choice of lesion, treatment time, and fluence rate etc. Despite much effort expended on the development of new photosensitizers (PS), there is still considerable uncertainty on the determinants for optimal efficacy. This may mean some patients receive sub-optimal treatment. The goal of this five-year program is an integrated multi-disciplinary investigation that embodies a translational bench-to-bedside approach to the optimization of PDT, with the hope of substantial improvements in therapeutic protocols with consequent patient benefit. The program has three unifying themes; a) looking at the PDT process in cellular, tissular and clinical milieus, and incorporating appropriate dosimetric and mechanistic feedback into treatment planning; b) modulating the various compartments of tumors including the cellular differentiation state to improve the PDT effect; c) studying the PDT process from intervention before PS delivery, through the immediate illumination, to the long term effects of the treatment. The projects focus on in vivo treatment in patients or murine models and include common PS and tumor types. Project 1 studies the effect of cellular differentiation on PS accumulation and PDT efficacy in skin and prostate cancer, and offers the hope of combining PDT with differentiation-inducing therapy. Project 2 comprises a clinical trial of ALA-PDT in Barrett?s esophagus with differentiating agents. Project 3 aims at providing on-line dosimetry based on tissue optics, PS concentrations and dynamic interactions with oxygen. Project 4 will investigate how PDT influences local control of tumors and distant metastasis; it will explore combination therapies that may significantly improve treatment outcome. Together with three Cores comprising a) an active Administration core with a Program website, b) a Pathology and Imaging core with fluorescence microscopy, c) an In vivo PDT: Animals, Dosimetry and Statistics core that will catalyze the integration of physicists and biologists, it is expected that this Program will make major progress in establishing determinants that make PDT effective in vivo.